N-(5-methylisoxazol-3-yl)-4-phenoxybutanamide

• 分子结构分类: 有机化合物 - 苯类化合物 - 苯酚醚
• 英文名称: N-(5-methylisoxazol-3-yl)-4-phenoxybutanamide
• 英文别名: N-(5-methyl-1,2-oxazol-3-yl)-4-phenoxybutanamide
• 化学式: C₁₄H₁₆N₂O₃
• mdl: MFCD03119586
• 分子量: 260.293
• InChiKey: AZVMWZHVCNRPFP-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.2
• 重原子数：
  19
• 可旋转键数：
  6
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.29
• 拓扑面积：
  64.4
• 氢给体数：
  1
• 氢受体数：
  4

反应信息

• 作为产物：
  描述：

  3-氨基-5-甲基异恶唑 、 4-苯氧基丁酸 在 4-二甲氨基吡啶 、 盐酸-N-乙基-Nˊ-(3-二甲氨基丙基)碳二亚胺 作用下， 以 1,2-二氯乙烷 为溶剂， 反应 16.0h， 以42%的产率得到N-(5-methylisoxazol-3-yl)-4-phenoxybutanamide
  参考文献：
  名称：

  Identification of 5-Substituted 2-Acylaminothiazoles That Activate Tat-Mediated Transcription in HIV-1 Latency Models

  摘要：

  The persistent reservoir of cells latently infected with human immunodeficiency virus (HIV)-integrated proviral DNA necessitates lifelong suppressive antiretroviral therapy (ART). Epigenetic targeted compounds have shown promise as potential latency-reversing agents; however, these drugs have undesirable toxicity and lack specificity for HIV. We utilized a novel HEK293-derived FlpIn dual-reporter cell line, which quantifies specific HIV provirus reactivation (LTR promoter) relative to nonspecific host cell gene expression (CMV promoter), to identify the 5-substituted 2-acylaminothiazole hit class. Here, we describe the optimization of the hit class, defining the functionality necessary for HIV gene activation and for improving in vitro metabolism and solubility. The optimized compounds displayed enhanced HIV gene expression in HEK293 and Jurkat 10.6 latency cellular models and increased unspliced HIV RNA in resting CD4+ T cells isolated from HIV-infected individuals on ART, demonstrating the potential of the 2-acylaminothiazole class as latency-reversing agents.

  DOI：

  10.1021/acs.jmedchem.9b00462

文献信息

• ACTIVATORS OF HIV LATENCY
  申请人：The Walter and Eliza Hall Institute of Medical Research

  公开号：US20190330167A1

  公开（公告）日：2019-10-31

  The present invention relates to novel compounds which active HIV expression in latently infected cells. More particularly, the invention relates to pharmaceutical compositions comprising the novel compounds and their use in activating HIV expression in latently infected cells. Further still, the invention relates to pharmaceutical compositions comprising the novel compounds in combination with anti-HIV therapy compounds and their use in treating HIV infection in both animals and humans. The invention further provides means for preparing the compounds.
• Identification of 5-Substituted 2-Acylaminothiazoles That Activate Tat-Mediated Transcription in HIV-1 Latency Models
  作者：William Nguyen、Jonathan Jacobson、Kate E. Jarman、Helene Jousset Sabroux、Leigh Harty、James McMahon、Sharon R. Lewin、Damian F. Purcell、Brad E. Sleebs

  DOI：10.1021/acs.jmedchem.9b00462

  日期：2019.5.23

  The persistent reservoir of cells latently infected with human immunodeficiency virus (HIV)-integrated proviral DNA necessitates lifelong suppressive antiretroviral therapy (ART). Epigenetic targeted compounds have shown promise as potential latency-reversing agents; however, these drugs have undesirable toxicity and lack specificity for HIV. We utilized a novel HEK293-derived FlpIn dual-reporter cell line, which quantifies specific HIV provirus reactivation (LTR promoter) relative to nonspecific host cell gene expression (CMV promoter), to identify the 5-substituted 2-acylaminothiazole hit class. Here, we describe the optimization of the hit class, defining the functionality necessary for HIV gene activation and for improving in vitro metabolism and solubility. The optimized compounds displayed enhanced HIV gene expression in HEK293 and Jurkat 10.6 latency cellular models and increased unspliced HIV RNA in resting CD4+ T cells isolated from HIV-infected individuals on ART, demonstrating the potential of the 2-acylaminothiazole class as latency-reversing agents.